Injector filled with an anti-cancer composition

ABSTRACT

An anti-cancer device having an anti-cancer drug and a blood coagulation factor fixed to a structure. This anti-cancer device is used in transcatheter arterial embolization and needle therapy with advantage and slowly releases the anti-cancer drug over an extended period by staying in the cancer tissue and its nearby area.

This is a continuation of application Ser. No. 466,190, filed Feb. 14,1983, now U.S. Pat. No. 4,536,387, issued Aug. 20, 1985.

FIELD OF THE INVENTION

The present invention relates to an anti-cancer device, and moreparticularly, to an anti-cancer device that can be used with advantagein treatment and diagnosis of cancers or tumors, such as transcatheterarterial embolization or needle therapy.

BACKGROUND OF THE INVENTION

Transcatheter arterial embolization has recently been recognized as aneffective method for treating liver cancer and breast cancer. Accordingto this method, one end of a catheter is inserted into a nutrient arteryleading to the cancer or tumoral tissue and a material that occludes thenutrient artery is injected through the other end of the catheter tostop the blood flow. This necroses the cancer or tumor tissue since itis not supplied with additional nutrient. Commonly assigned JapanesePatent Application (OPI) Nos. 135214/79 and 58163/80 (the symbol OPI asused herein means an unexamined published Japanese patent application)and U.S. Pat. No. 4,265,233 proposed materials for wound protection andhealing that have blood coagulation Factor XIII and thrombin fixedthereto. It has been reported (as in the 18th Conference of JapaneseSociety for Artificial Organs and Tissues) that these materials areeffectively used as occluding materials in transcatheter arterialembolization. But one great disadvantage of the transcatheter arterialembolization technique is that it cannot be supplemented withchemotherapy which is another effective way to treat cancers or tumors.After transcatheter arterial embolization, administering an anti-tumoragent orally or by injection is meaningless since the nutrient arteryhas been closed to prevent the agent from reaching the cancer or tumoraltissue. Therefore, if transcatheter arterial embolization is effected,the surgeon either abandons chemotherapy or occludes the nutrient arteryafter injecting an anti-cancer agent through a catheter inserted intothe artery. Buy this two-step method is not very effective since theapplied anti-cancer agent runs away in an extremely short time to sitesother than the target cancer or tumor tissue; for one thing, the agentis usually administered in solution and its amount is not very great,and for another, the nutrient artery has not been completely occluded.Therefore, the incompatibility with chemotherapy, the biggest problemwith the transcatheter arterial embolization technique, is yet to besolved, and a new pharmaceutical preparation that is free from thisdefect is in great demand.

There is another technique that is considered to be promising as amethod of treating cancer, and this is needle therapy. The term needletherapy as conventionally used means drawing body fluids through ahollow needle, but needle therapy as used hereunder relates to a methodof examining and treating cancer or tumor tissue. Examination by needletherapy is generally referred to as biopsy and consists of examining asample of body tissues. For application to the examination of cancer ortumor tissues, this technique consists of collecting a doubtful tissuewith a needle and subjecting it to diagnostic examination. Two problemshave been pointed out in connection with this technique. One is that thecancer or tumor tissue collected on the tip of the needle maycontaminate normal tissue as the needle is withdrawn, and no effectivemethod is available for avoiding this trouble. The other problem isbleeding. Unlike transcatheter arterial embolization wherein a catheteris inserted into a blood vessel, needle therapy involves piercing thebody with a needle to reach the target tissue and causes bleeding fromthe damaged site. If the damaged site is normal, bleeding stopsspontaneously and the damaged blood vessel is repaired in a fairly shortperiod and there will be no adverse postoperative effect. But the canceror tumoral tissue lacks ability to stop bleeding and repair a damagedblood vessel, and this is usually so with the neighboring tissues.Therefore, they have a great tendency to bleed during needle therapy andonce they bleed, it is difficult to stop the bleeding. If seriousbleeding is expected, the very operation by needle therapy must beabandoned. The problem of bleeding is particularly great with a spleen,which is rarely subjected to needle therapy. In most cases of needletherapy, the needle with the target tissue on its tip is withdrawn whilea proper method is being applied to stop bleeding. The common method ofachieving this object is to inject an aqueous solution of thrombinduring the withdrawing of the needle. But even this method is notcompletely satisfactory since the ability of thrombin to stop bleedingis not very great and the thrombin, being liquid, runs away from thesite that is damaged and needs repairing. The second type of needletherapy which is directed to treatment of cancer or tumor tissuesconsists of directly injecting an anti-cancer agent through a needleinto the target tissue. Since the needle currently used in thistechniuqe is as fine as 19G to 23G, the only anti-cancer agent that canbe inejcted is antibiotics and other drugs in solution. But if theanti-cancer agent in solution is injected through the needle, itimmediately departs from the target tissue and the purpose of topicalapplication of the drug is not achieved. Therefore, it has long beendesired to develop a therapeutic preparation that can be injectedthrough a very fine needle (19-23 G) into the target tissue and the areaaround the injection pathway and which stays at the injected site aslong as it slowly releases the active agent.

SUMMARY OF THE INVENTION

Therefore, a general object of the present invention is to provide ananti-cancer device that can be used in both transcatheter arterialembolization and needle therapy. When the device is used intranscatheter arterial embolization, it is capable of rapid and reliableocclusion of the blood vessel and lets the active ingredient effectivelyact on the target cancer or tumor tissue for an extended period. Whenthe device is applied to needle therapy, it stops bleeding quickly andreliably and repairs the damaged blood vessel in an early period.Furthermore, the device permits the active substance to work effectivelyon the cancer or tumor tissue that is most likely to contaminate thearea around the route along which the needle is to be withdrawn.

As a result of various studies to attain the stated object, the presentinventors have found that a structure having an anti-cancer drug and ablood coagulation factor fixed thereto has high ability to occlude ablood vessel, stop bleeding and repair a damaged blood vessel. Theinventors have also found that once it has reached the target site (thecancer or tumor tissue to be treated), the structure stays there as wellas the nearby area without being washed away with blood or body fluids,and keeps slowly releasing the anti-cancer drug over an extended period.The present invention therefore provides an anti-cancer devicecomprising a structure comprised of a polymer, an anti-cancer drug, anda blood coagulation factor, wherein the anti-cancer drug and bloodcoagulation factor are fixed to the structure in such a manner as to becapable of sustained release from the structure.

Within this specification, the term "device" refers to any structuresuch as fibrous assembly, sponge, powder, monofilament, film andmicrocapsule, having fixed thereto an anti-cancer drug and a bloodcoagulation factor, the anti-cancer drug and blood coagulation factorbeing fixed to the structure in such a manner as to permit its sustainedrelease.

DETAILED DESCRIPTION OF THE INVENTION

The structure used in the present invention may be made up of syntheticpolymers such as silicone, polyesters, polyamides, polyurethanes,polyacrylonitrile, polyacrylamide, polyacrylic acid esters,polyethylene, polypropylene, polyvinyl chloride and polyvinyl alcohol;cellulosic materials and their derivatives such as cotton, hemp, pulp,ethyl cellulose and cellulose acetate; regenerated cellulose such asviscose rayon and caprammonium rayon; and various bioabsorbablematerials. Illustrative bioabsorbable materials include polysaccharidessuch as amylose, oxidized cellulose, dextran, chitin and pullulan;collagen, gelatin, polyglutamic acid and their ester derivatives withhydroxyethylbenzyl, etc.; polyamino acids such as polylysine,polyaspartic acid and polyphenylalanine; polyglycolic acid, polylacticacid, glycolic acid-polylactic acid copolymer; and polyesters ofsuccinic acid and polyesters of oxalic acid. Because of theirnontoxicity to humans, silicone, cellulose derivatives and bioabsorbablematerials are preferred.

In many cases, the anti-cancer device of the present invention is nottaken out of the human body after it is injected into the target site.Therefore, the structure is preferably made up of a material that is notleft unabsorbed by the tissue, and in this respect, bioabsorbablematerials such as gelatin, chitin, collagen, amylose, polyglycolic acid,polylactic acid and oxidized cellulose are particularly preferred, morepreferably gelatin, chitin and oxidized cellulose.

The anti-cancer drug as used in the present invention means thosechemotherapeutic agents commonly called anti-tumor agents and thosewhich are referred to as immunotherapeutics or immunoactivators. Amontthe first type of durgs are included alkylating agents such as Nitrogenmustards, nitromin, chlorambucil, cyclophosphamide, melphalan, uracilmustard, mannomustine, dopan, BCNU, triethylenemelamine, thio-TEPA,Aza-TEPA, threnimone, inprocuon, busulfan, dimethylmilelane, piposulfan,ethoglucide, epoxypropidine, epoxypiperazine, hexamethylmelamine,dibromomannitol, pipobroman, CCNU, methyl-CCNU, chlorozotocin, GANU,MCNU, ACNU, TA-077 and fosamid; antimetabolites such as folic acid,aminopterin, methotrexate, guanine, 8-azaguanine, 6-mercaptopurine,azathioprine, uracil, 5-fluorouracil, cytarabine, azaserine, diazamycin,BHAC, SM108, cispuracham, cytosine arabinoside, tegaful, HCFU, 5'DFUR,TK-117 and cyclotidine; antibiotics such as actinomycin D, cyclomycin,mitomycin C, daunomycin, bleomycin, cromomycin, carzinophyllin,macrocinomycin, neothramycin, thalisomycin, sporamycin, saframycin,ansamytocin, DON, macromomycin, nogaromycin,7-o-methylnogallol-4'-epiadriamycin, streptozotocin,4-demethoxydaunorubicin and mitozanthron; synthetic agents such as 5-HPand IQ-1; plant components such as thiotepa, cyclophosphamide,doxorubicin, daunorubicin and neocarzinostain; and Hg-hematoporphyrine,Co-protoporphyrine, stillbestrol, hydroxyurea, procarbazine,methylglyoxalbis-guanylhydrazone, L-asparaginase and TNF. Thesechemotherapeutic agents may be used either alone or in combination.Commonly, one alkylating agent, one antimetabolite and one antibioticare combined, and more commonly, cyclophosphamide, 5-fluorouracil andmitomycin or bleomycin are combined.

Illustrative immunotherapeutics or immunoactivators include thymichormones and their related substances, BCG, skeletal cell walls andtheir methanol-insoluble fractions, microorganism such asCorynebacterium parvum and OK-432 and their components; polysaccharidessuch as picivanil, lentinan, SPG, mannan, levan and glucan; muramyldipeptide and its derivatives; levamisole, pestatin, isoprinocin, NPT15392, azimecrin, transfer factors, lymphokain, immuno-RNA, interferonsand their inducers and vaccines such as Maruyama vaccine. Theseimmunotherapeutics or immunoactivators may be used either alone or incombination. Commonly, they are used in combination with theabove-listed anti-tumor agents.

In the present invention, bleomycin, mitomycin C, adriamycin and5-fluorouracil are preferred since their effectiveness in controllingcancer are widely recognized and their high toxicity requires topicalrather than systemic administration.

Examples of the blood coagulation factor that can be used in the presentinvention include coagulation factors I, II, III, IV, V, VII, VIII, IX,X, XI, XII and XIII, as well as prekallikrein, high-molecular weightkininogen and thrombin. These factors may be used either alone or incombination. In the present invention, coagulation factor XIII(hereunder abbreviated to F XIII) and thrombin are preferred, and thecombination of F XIII and thrombin is most preferred. F XIII is referredto as a fibrin stabilizing factor and promotes the stabilization ofinstable fibrin by forming isopeptide linkages between the fibrinmolecules. F XIII is isolated from the blood or placenta of man andcattle. For application to a human, the use of F XIII derived fromhumans is preferred. Thrombin is a protease capable of convertingfibrinogen to fibrin. It is isolated from the blood of man, cattle,swine, etc., and for application to man, the use of human thrombin ispreferred.

The anti-cancer drug and blood coagulation factor that are used in thepresent invention can be fixed to the structure by bonding, adsorptionor encapsulation. The anti-cancer drug and blood coagulation factor canbe bonded to the structure by known methods of covalent bonding and ionbonding as described in O. Zaborsky, "Immobilized Enzymes", CRC Press,1973. The anti-cancer drug and blood coagulation factor may be adsorbedon the structure either by physical adsorption or entrapping. Forencapsulation, the anti-cancer drug and blood coagulation factor may beenclosed with an outer wall of the structure-making material by a knownmethod of microcapsulation.

More specifically, to prepare the anticancer device of the presentinvention, the anti-cancer drug and blood coagulation factor may bebound to the structure by either of the following methods. When theanti-cancer drug and blood coagulation factor each contain a functionalgroup capable of forming a covalent or ionic bond (e.g., an amino groupor carboxyl group), a solution containing them may be used to treat thestructure containing functional groups capable of covalent bonding orionic bonding with these functional groups, and by so doing, they arefixed to the structure. When the structure contains few or no functionalgroups capable of covalent bonding or ionic bonding to the functionalgroup in the anti-cancer drug or blood coagulation factor, the lattermay be bonded to the structure after chemically introducing thenecessary group into the structure. If the anti-cancer drug or bloodcoagulation factor has no functional group, it may also be used afterchemically introducing a functional group, but in most cases, thismethod is not advantageous since the chemical reaction used to introducethe necessary functional group impairs the therapeutical characteristicsof the anticancer drug or blood coagulation factor. In the case ofcovalent bonding, it is preferred to use a dehydrocondensation agentsuch as dicyclohexyl carbodiimide,1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide-metho-p-toluenesulfonate.

In this case the dehydro-condensation agent is dissolved in an amount ofabout 0.1 to 20% by weight, preferably about 1 to 10% by weight, inwater or a mixture of water with a water-miscible solvent such as methylalcohol, ethyl alcohol, propyl alcohol, dioxane, tetrahydrofuran,dimethylformamide or dimethyl sulfoxide. A structure is treated with amixed solution of the dehydro-condensation agent solution and theanti-cancer drug and blood coagulation factor solution, or first withthe dehydro-condensation agent solution and subsequently with theanti-cancer drug and blood coagulation factor solution or vice versa, ata temperature of about -20° C. to about 60° C., preferably 0° to 40° C.,for about 10 min. to about 72 hrs., preferably for 30 min. to 24 hrs.

Fixation of anti-cancer drug and blood coagulation factor to thestructure having a functional group or an ion exchange group to therebycovalently or ionically bond is performed by treating the structure witha solution of the anti-cancer drug and blood coagulation factor.Fixation of anti-cancer drug and blood coagulation factor is carried outby treating the structure with a solution containing the anti-cancerdrug and blood coagulation factor, or by first treating it with asolution of anti-cancer drug and subsequently with a solution of bloodcoagulation factor, or in the reverse order.

In these methods, in view of ease of operation the method of treatingthe structure with solvent containing both the anti-cancer drug andblood coagulation factor is preferred, but in view of the prevention ofthe condensation and activity reduction thereof the method of treatingseparately it with a solution containing anti-cancer drug or a solutioncontaining blood coagulation factor is preferred. Anti-cancer drug andblood coagulation factor dissolve in water or a mixture of water withwater-miscible solvent such as methanol, ethanol, propanol, acetone,tetrahydrofuran, dioxane, dimethyl sulfoxide or dimethylformamide. Asuitable temperature for the fixation is about -20° C. to 70° C.,preferably about 0° to 40° C., and suitable treating time is about 1min. to 48 hrs., preferably about 2 min. to 24 hrs. In fixinganti-cancer drug and blood coagulation factor, the pH of the solutionshould be adjusted to about 3 to about 10, preferably 4 to 9.

In producing the anti-cancer device of this invention, anti-cancer drugand blood coagulation factor can be fixed to the structure in the formof a monofilament, a fibrous assembly, a film, a microcapsule, a powderor a sponge or the like by adsorption in the following manner. As a formof these structures, a powder and a sponge are preferred. Adsorption ofanti-cancer drug and blood coagulation factor can be carried out bytreating the structure with solvent containing the anti-cancer drug andblood coagulation factor which are dissolved, emulsified or suspended ina solvent capable of wetting the structure, or by first treating it witha solution containing anti-cancer drug and subsequently with a solutioncontaining blood coagulation factor, or in the reverse order.

In these methods, in view of ease of operation the method of treatingthe structure with solvent containing both the anti-cancer drug andblood coagulation factor is preferred, but in view of the prevention ofthe condensation and activity reduction thereof the method of treatingseparately it with a solution containing anti-cancer drug or a solutioncontaining blood coagulation factor is preferred. Adsorption is carriedout at a temperature of about -20° C. to 60° C., preferably about 0° to40° C., for a period of about 1 min. to 72 hrs., preferably about 3 min.to 24 hrs. Suitable solvents are water and mixtures of water andwater-miscible solvents such as methanol, ethanol, propanol, acetone,tetrahydrofuran, dioxane, dimethyl sulfoxide and dimethylformamide.

Anti-cancer device of this invention can also be produced by fixinganti-cancer drug and blood coagulation factor by entrapping. Entrappingcomprises entrapping anti-cancer drug and blood coagulation factor inthe fine lattices of a gel or in a polymeric film. Suitable materialsused in the adsorption or entrapping method are adsorbable materialssuch as collagen, gelatin, polyglycolic acid, polylactic acid, aglycolic acid/lactic acid copolymer, polyglutamic acid, amylose andchitin.

The amount of anti-cancer drug and blood coagulation factor fixed to thestructure varies over a wide range in accordance with a type ofsustained release, the time for which the anti-cancer device is used andthe form of the anti-cancer device.

However, generally, the amount of the anti-cancer drug fixed is 0.001 to1,000 mg per 1 mg of the structure and the amount of the bloodcoagulation factor fixed is 0.001 to 100 mg per 1 mg of the structure.The preferred amounts of the anti-cancer drug and blood coagulationfactor fixed to the structure vary in accordance with a kind thereof.For example, the amounts of mitomycin C, bleomycin, adriamycin,5-fluorouracil, F XIII and thrombin are preferably 0.001 to 200 mg, 0.01to 100 mg, 0.001 to 200 mg, 0.001 to 1,000 mg, 0.001 to 50 mg and 0.01to 100 mg per 1 mg of the structure, respectively. When the anti-cancerdevice is allowed to stand in human plasma at 37° C., the fixedanti-cancer drug and blood coagulation factor can be released from theanti-cancer device for 1 hour or more, 5 hours or more, 10 hours ormore, 24 hours or more, or 2 days or more.

The anti-cancer device of the present invention may be produced bymethods other than bonding or adsorbing the anti-cancer drug and bloodcoagulation factor to the structure or entrapping the former in thelatter. For instance, the anti-cancer drug and blood coagulation factormay be bonded or adsorbed on or entrapped in the raw material of thestructure, and the resulting product is processed into a predeterminedform of the structure. In one embodiment of this modification, theanti-cancer drug is first bonded or adsorbed on, or entrapped in, apolymeric material to form the desired structure which is given thenecessary treatment into the anti-cancer device of the presentinvention. Alternatively, a structure to which the anti-cancer drug isfixed and another structure to which the blood coagulation factor isfixed may be assembled to form the anti-cancer device of the presentinvention. In this case, the two structures, instead of being assembled,may be kept separate until use, whereupon they are mixed by suspendingin a physiological saline solution and serve as the anti-cancer deviceof the present invention.

In the production of the anti-cancer device of this invention, a calciumion which participates in the activation of the blood coagulationreaction can be fixed together with the anti-cancer drug and bloodcoagulation factor. The calcium ion is generally added to the structureas calcium chloride in an amount of 0.1 μmol to 1 mmol, preferably 0.5μmol to 200 μmol.

In addition to the anti-cancer drug and blood coagulation factor,various pharmaceuticals may be fixed to the structure, and suitablepharmaceuticals include protease inhibitors such as antiplasmin, albuminand alpha₂ -macroglobulin; plasma proteins such as ceruloplasmin,haptoglobin and cold insoluble globulin (CIG); and fibronectin,antibiotics, antivirals, sulfamides and antiinfectives. CIG andfibronectin are believed to have affinity for cancer tissues or abilityto inhibit their growth, and hence, together with the anti-cancer deviceof the present invention, are expected to enhance the effect of theanti-cancer drug. Antiplasmin is an inhibitor of plasmin, a fibrinolyticenzyme, and also enhances the effectiveness of the anti-cancer device ofthe present invention. Preferred antiplasmins are α-aminocaproic acidand tranexamic acid.

Since such pharmaceutical fixed to the structure together withanti-cancer drug and blood coagulation factor varies in a wide range inaccordance with a kind of pharmaceutical, the desired effects and thetime of which the anti-cancer device is used, it is not practical todetermine the range of the amount of the pharmaceutical. However,generally, the amount of the pharmaceutical fixed thereto is 1 microgramto 100 milligram per 1 g of the anti-cancer device, preferably 10microgram to 10 milligram.

The anti-cancer device of the present invention is preferably used intreating cancers or tumors, and it is particularly preferred to use itin transcatheter arterial embolization or needle thereapy. Intranscatheter arterial embolization, one end of a catheter is insertedinto a nutrient artery leading to the target cancer or tumor tissue anda suspension of the anti-cancer device in a physiological salinesolution is injected from the other end of the catheter. Part of theinjected device reaches not only the target tissue but also the nearbytissue and stays there, and the other part of the device, serving as anoccluding material, stays within the nutrient vessel to occlude it. Theoccluded vessel will not open again. The anti-cancer device withsustained release staying on the target tissue, its neighboring area andwithin the occluded vessel releases the effective compound to topicallyact on the cancer or tumor tissue for an extended period, thusaccomplishing rapid and reliable necrosis of the malignant tissue. Thismeans that a rapid and reliable operation by transcatheter arterialembolization is possible with the anti-cancer device with sustainedrelease of the present invention and that it can be supplemented with achemotherapeutic technique that is conventionally incompatible with thetranscatheter arterial embolization technique.

In needle therapy, a needle is pierced through the skin to the targetcancer or tumor tissue, and the necessary amount of a suspension in aphysiological saline of the anti-cancer device of the present inventionis injected into the target tissue, and then the needle is withdrawn asmore suspension is introduced. In consequence, the anti-cancer device ofthe present invention is topically administered to the target tissue andthe tissue about the needle's route, and because of the fibrin networkformed by the blood coagulation factor fixed to the structure, thedevice stays in the injected area. The device immediately stops thebleeding and repairs the damaged site of the blood vessel, and at thesame time, it slowly releases the active compound to work effectively onthe cancer or tumor tissue over a prolonged period. The anti-cancerdevice that has been injected as the needle is being withdrawn and whichstays on the tissue around the needle's path also immediately stops thebleeding of the damaged blood vessel in the nearby tissue and reparisthe damage. At the same time, the device releases the active compoundthat has long-lasting effectiveness on the cancer or tumor cells thatcontaminate the tissue around the needle's pathway.

As described in the foregoing, the anti-cancer device of the presentinvention is effectively used in transcatheter arterial embolization andneedle therapy, wherein it serves as an excellent agent that not onlyoccludes blood vessels but also lets an anti-cancer drug be releasedover a prolonged period. Since the anti-cancer device of the presentinvention is administered topically, the problem that may be caused bythe strong toxicity of the drug can be avoided. The advantage of theanti-cancer device of the present invention is also apparent when it isused in therapies other than transcatheter arterial embolization andneedle therapy. For instance, it may be dusted over a cancer tissue thathas been exposed by a surgical operation; the applied device immediatelysticks to the tissue and will not be washed away by blood or bodyfluids.

The present invention is now described in greater detail by reference tothe following examples which are given here for illustrative purposesonly and are by no means intended to limit the scope of the invention.

EXAMPLE 1

Two hundred milligrams of absorbable gelatin powder (Gelfoam, JapanUpjohn Ltd.) was immersed for 5 minutes at room temperature in a mixtureof 4 ml of an aqueous Fibrogamin solution (prepared by dissolving abottle of concentrated dry human F XIII of Hoechst Aktiengesellschaft in4 ml of water), 5 ml of a physiological saline solution of thrombin(prepared by dissolving a bottle of concentrated dry human thrombin ofThe Green Cross Corporation in 5 ml of physiological saline) and 4 ml ofan aqueous solution of mitomycin C (20 mg/4 ml), and the resultingsuspension was freeze-dried at -30° C. for 15 hours to prepare a Gelfoamwherein 240 units of F XIII, 500 units of thrombin and 20 mg ofmitomycin C were fixed to gelatin through ionic bonding, entrapping andadsorption.

A loop of medical silicone tube (length: 34 cm long, ID: 4 mm) in a room(2° C.) was filled first with a mixture of ACD stored blood (2 ml) and10 wt % aqueous CaCl₂ solution (1 ml), then with 20 mg of the previouslyprepared Gelfoam. The resulting sample was placed on a rotary plateinclined at an angle of 23 degrees and was rotated at 16 rpm. One minutelater, a clot formed, and the rotation of the plate was stopped. Onehour later, a paper disc for testing antibiotics (8 mm in diameter)produced by Toyo Engineering Works, Ltd. was thoroughly immersed in theblood or placed into intimate contact with the clot in the loop andsubjected to a culture test with Bacillus subtilis ATCC 6633 by thecylinder-tray method. The size of the resulting inhibition zoneindicated that the concentration of mitomycin C in blood for the firsthour was 10 μg/mg. The same measurement was made 5 hr, 10 hr, 24 hr, 1.5days, 2 days and 3 days after the stoppage of the rotation of the bloodsample. The respective concentrations of mitomycin C in blood were 15μg/mg, 21 μg/mg, 41 μg/mg, 82 μg/mg, 112 μg/mg and 198 μg/mg.

COMPARATIVE EXAMPLE 1

Twenty milligrams of Gelfoam having mitomycin C fixed to gelatin wasprepared by repeating the procedure of Example 1 except that neither FXIII nor thrombin was used. It was placed on a rotary loop as in Example1 and subjected to a coagulation test, followed by measurement of theconcentration of mitomycin C in blood. No clot formed even after 3 hoursof rotation of the loop, and the concentration of mitomycin C in bloodat that time was 600 μg/ml. This indicates that having no sustainedrelease, the Gelfoam released almost all of mitomycin C into the bloodwithin 3 hours.

EXAMPLE 2

Two hundred milligrams of absorbable gelatin powder (Gelfoam, JapanUpjohn Ltd.) was immersed in 4 ml of an aqueous Fibrogamin solution(prepared by dissolving a bottle of concentrated dry human F XIII ofHoechst Aktiengesselschaft in 8 ml of water) for 3 minutes at roomtemperature, and then freeze-dried at -30° C. for 15 hours. Thefreeze-dried product was immersed for 5 minutes at room temperature in asuspension of 25 mg of 5-fluorouracil in 4 ml of dimethylformamide, andfreeze-dried at -30° C. for 15 hours to prepare a Gelfoam wherein 240units of F XIII and 20 mg of 5-fluorouracil were fixed to gelatinthrough ionic bonding, entrapping and adosrption. Twenty milligrams ofthe sample was placed on a rotary loop and subjected to a coagulationtest as in Example 1. One minute and a half after the loop started torotate, a clot formed. The rotation of the loop was stopped and 50 μg ofblood or clot was sampled 5 hr, 10 hr, 24 hr, 1.5 days, 2 days and 3days later. The samples were freeze-dried and their 5-fluorouracilconcentrations in blood were determined by measuring the weight of5-fluorouracil in the respective samples by the oxygen flask combustionmethod using a mixture of sodium hydroxide and water as an absorbent:the respective values were 12 μg/mg (5 hr), 17 μg/mg (10 hr), 38 μg/mg(24 hr), 78 μg/mg (1.5 days), 101 μg/mg (2 days) and 162 μg/mg (3 days).

EXAMPLE 3

Twenty milligrams of chitin powder having 240 units of F XIII, 500 unitsof thrombin and 20 mg of mitomycin C fixed to chitin by ionic bonding,entrapping and adsorption was prepared by repeating the procedure ofExample 1 except that the Gelfoam was replaced by chitin powder (mol.wt. 1,000,000, Kyowa Yushi Co., Ltd.). It was subjected to a coagulationtest with a rotary loop as in Example 1. One minute after the loopstarted to rotate, a clot formed and the blood in the loop became nolonger fluid. The rotation of the loop was stopped and the concentrationof mitomycin C in blood was measured 1 hr, 5 hr, 10 hr, 24 hr, 1.5 days,2 days and 3 days later: the respective values were 8 μg/ml, 14 μg/ml,19 μg/ml, 38 μg/ml, 78 μg/ml, 108 μg/ml and 178 μg/ml.

EXAMPLE 4

A sheet of absorbable gelatin sponge (Spongel, Yamanouchi PharmaceuticalCo., Ltd.) measuring 2.5 cm×5 cm×0.5 cm was immersed for 5 minutes atroom temperature in a solution having 200 mg of bleomycin and 20 mg of1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide-metho-p-toluenesulfonatedissolved in a physiological saline solution of thrombin (prepared bydissolving a bottle of thrombin in 10 ml of physiological saline), andthe resulting supsension was freeze-dried at -30° C. for 15 hours toproduce a Spongel wherein 500 units of thrombin and 190 mg of bleomycinwere fixed to gelatin through covalent bonding, adsorption andentrapping. Twenty milligrams of the Spongel was placed on a rotary loopand subjected to a coagulation test as in Example 1. One minute afterthe loop was started to rotate, a clot formed. The rotation of the loopwas then stopped and the concentration of bleomycin in blood wasmeasured 1 hr, 5 hr, 10 hr, 24 hr, 1.5 days, 2 days and 3 days later:the respective values were 5 μg/mg, 7 μg/mg, 11 μg/mg, 21 μg/mg, 41μg/mg, 62 μg/mg and 123 μg/mg.

EXAMPLE 5

One gram of ethyl cellulose beads (ca. 250 microns in diameter) wereimmersed in 100 g of 2 wt % aqueous aminoacetal solution at 60° C. for 8hours. The beads were recovered, washed with water, immersed in 100 g ofa 4 wt % acetone solution of methyl vinyl ethermaleic anhydridecopolymer (Gantrez AN-169 of GAF Corporation) for 2 hours at roomtemperature and washed with acetone. The washed beads were dried and 150mg of them was immersed in 4 ml of an aqueous Fibrogamin solution(prepared by dissolving a bottle of concentrated dry human F XIII ofHoechst Aktiengesselschaft in 9 ml of water) for 3 mintues at roomtemperature, and then freeze-dried at -30° C. for 15 hours. Thefreeze-dried product was immersed in a suspension of 25 mg of5-fluorouracil in 4 ml of dimethylformamide for 5 minutes at roomtemperature, and freeze-dried at -30° C. for 15 hours to prepare ethylcellulose beads wherein 240 units of F XIII and 25 mg of 5-fluorouracilwere fixed to cellulose primarily by covalent bonding. Twenty milligramsof the sample was placed on a rotary loop and subjected to a coagulationtest as in Example 1. One minute and a half after the loop started torotate, a clot formed. The rotation of the loop was stopped and 50 μg ofblood or clot was sampled 5 hr, 10 hr, 24 hr, 1.5 days, 2 days and 3days later. The samples were freeze-dried and their 5-fluorouracilconcentrations in blood were determined by measuring the weight of5-fluorouracil in the respective samples by the oxygen flask combustionmethod using a mixture of sodium hydroxide and water as an absorbent:the respective values were 3.5 μg/mg, 5.5 μg/mg, 10.0 μg/mg, 21.5 μg/mg,31.5 μg/mg and 60.0 μg/mg.

EXAMPLE 6

Two hundred milligrams of nylon sponge cut to lengths of about 500μ wasimmersed for 5 minutes at room temperature in a mixture of an aqueousFibrogamin solution (prepared by dissolving a bottle of concentrated dryhuman F XIII of Hoechst Aktiengesellschaft in 4 ml of water), 4 ml of aphysiological saline solution of thrombin (prepared by dissolving abottle of concentrated dry human thrombin of The Green Cross Corporationin 5 ml of physiological saline) and 4 ml of an aqueous solution ofmitomycin C (20 mg/4 ml), and the resulting suspension was freeze-driedat -30° C. for 15 hours to prepare a nylon sponge wherein 200 units of FXIII, 450 units of thrombin and 20 mg of mitomycin C were fixed to nylonthrough ionic bonding, entrapping and adsorption.

A loop of medical silicone tube (length: 34 cm, ID: 4 mm) in a room (2°C.) was filled first with a mixture of ACD stored blood (2 ml) and 10 wt% aqueous CaCl₂ solution (1 ml), then with 20 mg of the previouslyprepared nylon sponge. The resulting sample was placed on a rotary plateinclined at an angle of 23 degrees and was rotated at 16 rpm. One minutelater, a clot formed, and the rotation of the plate was stopped. Onehour later, a paper disc for testing antibiotics (8 mm in diameter)produced by Toyo Engineering Works, Ltd. was thoroughly immersed in theblood or placed into intimate contact with the clot in the loop andsubjected to a culture test with Bacillus subtilis ATCC 6633 by thecylinder-tray method. The size of the resulting inhibition zoneindicated that the concentration of mitomycin C in blood for the firsthour was 10 μg/mg. The same measurement was made 5 hr, 10 hr, 24 hr, 1.5days, 2 days and 3 days after the stoppage of the rotation of the bloodsample. The respective concentrations of mitomycin C in blood were 15μg/mg, 21 μg/mg, 41 μg/mg, 82 μg/mg, 112 μg/mg and 198 μg/mg.

COMPARATIVE EXAMPLE 2

Twenty milligrams of nylon sponge having mitomycin C fixed to nylon wasprepared by repeating the procedure of Example 6 except that neither FXIII nor thrombin was used. It was placed on a rotary loop as in Example6 and subjected to a coagulation test, followed by measurement of theconcentration of mitomycin C in blood. No clot formed even after 3 hoursof rotation of the loop, and the concentration of mitomycin C in bloodat that time was 600μg/ml. This indicates that having no sustainedrelease, the nylon sponge released almost all of mitomycin C into theblood within 3 hours.

EXAMPLE 7

Polyethylene terephthalate beads (ca. 250 microns in diameter) wereimmersed in a mixture of 10 wt % aqueous polyethyleneimine and methanolwhose volume was 5 times as much as that of the aqueouspolyethyleneimine, and they were left to stand at room temperature for30 minutes. A methanol solution of 5 wt % dicyclohexylcarbodiimide whosevolume was twice that of the aqueous polyethyleneimine was added, andthe beads were held at room temperature for two more hours. The beadswere then washed with water, dried, immersed in an acetone solution of 4wt % methyl vinyl ether-maleic anhydride copolymer at room temperaturefor 2 hours, and washed with acetone. The washed beads were dried and200 mg of them was immersed in 4 ml of an aqueous Fibrogamin solution(prepared by dissolving a bottle of concentrated dry human F XIII ofHoechst Aktiengesselschaft in 8 ml of water) for 3 minutes at roomtemperature, and then freeze-dried at -30° C. for 15 hours. Thefreeze-dried product was immersed in a suspension of 25 mg of5-fluorouracil in 4 ml of dimethylformamide for 5 minutes at roomtemperature, and freeze-dried at -30° C. for 15 hours to preparepolyethylene terephthalate beads wherein 180 units of F XIII and 20 mgof 5-fluorouracil were fixed to polyethylene terephthalate primarily bycovalent bonding. Twenty milligrams of the sample was placed on a rotaryloop and subjected to a coagulation test as in Example 6. One minute anda half after the loop started to rotate, a clot formed. The rotation ofthe loop was stopped and 50 μg of blood or clot was sampled 5 hr, 10 hr,24 hr, 1.5 days, 2 days and 3 days later. The samples were freeze-driedand their 5-fluorouracil concentrations in blood were determined bymeasuring the weight of 5-fluorouracil in the respective samples by theoxygen flask combustion method using a mixture of sodium hydroxide andwater as an absorbent: the respective values were 3.0 μg/mg (5 hr), 5.0μg/mg (10 hr), 9.5 μg/mg (24 hr), 20.0 μg/mg (1.5 days), 29.5 μg/mg (2days) and 58.5 μg/mg (3 days).

EXAMPLE 8

Nylon beads wherein 180 units of F XIII and 200 mg of 5-fluorouracilwere fixed to nylon primarily by covalent bonding were prepared as inExample 7 except that the polyethylene terephthalate beads were replacedby nylon beads (ca. 200 microns in diameter). Twenty milligrams of thebeads was subjected to a coagulation test with a rotary loop as inExample 6. One minute after the loop started to rotate, a clot formedand the blood became no longer fluid. The rotation of the loop was thenstopped and the concentration of 5-fluorouracil in blood was measured 1hr, 5 hr, 10 hr, 24 hr, 1.5 days, 2 days and 3 days later: therespective values were 1.5 μg/mg, 3.5 μg/mg, 5.5 μg/mg, 10.5 μg/ml, 20.5μg/ml, 30.0 μg/ml and 58.5 μg/ml.

EXAMPLE 9

Square sheets (500×500μ) of nylon taffeta were immersed for 5 minutes atroom temperature in a solution having 200 mg of bleomycin and 20 mg of1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide-metho-p-toluenesulfonatedissolved in a physiological saline solution of thrombin (prepared bydissolving a bottle of thrombin in 10 ml of physiological saline), andthe resulting suspension was freeze-dried at -30° C. for 15 hours toproduce a nylon taffeta wherein thrombin and bleomycin were fixed tonylon primarily by covalent bonding. Twenty milligrams of the taffetawas placed on a rotary loop and subjected to a coagulation test as inExample 6. One minute after the loop started to rotate, a clot formed.The rotation of the loop was then stopped and the concentration ofbleomycin in blood was measured 1 hr, 5 hr, 10 hr, 24 hr, 1.5 days, 2days and 3 days later: the respective values were 2.0 μg/mg, 4.0 μg/mg,6.0 μg/mg, 10.5 μg/mg, 21.5 μg/mg, 31.0 μg/mg and 59.5 μg/mg.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. An injector filled with a compositioncomprising:(a) a polymer, wherein said polymer has fixed thereto; (b) ananti-cancer drug; and (c) a blood coagulation factor, wherein saidanti-cancer drug and said blood coagulation factor are fixed to saidpolymer so as to be capable of sustained release from the polymer at thesite of injection and wherein said composition is useful fortranscatheter arterial embolization and needle therapy.
 2. The injectoras claimed in claim 1, wherein said polymer is a synthetic polymer. 3.The injector as claimed in claim 2, wherein said synthetic polymer issilicone.
 4. The injector as claimed in claim 1, wherein said polymer isselected from the group consisting of cellulosic material, cellulosicmaterial derivative and regnerated cellulose.
 5. The injector as claimedin claim 4, wherein said cellulosic material derivative is ethylcellulose.
 6. The injector as claimed in claim 1, wherein said polymeris bioabsorable material.
 7. The injector as claimed in claim 6, whereinsaid bioabsorable material is polysaccharide.
 8. The injector as claimedin claim 7, wherein said polysaccharide is amylose.
 9. The injector asclaimed in claim 7, wherein said polysaccharide is oxidized cellulose.10. The injector as claimed in claim 7, wherein said polysaccharide ischitin.
 11. The injector as claimed in claim 6, wherein saidbioabsorable material is collagen.
 12. The injector as claimed in claim6, wherein said bioabsorable material is gelatin.
 13. The injector ascalimed in claim 6, wherein said bioabsorable material is polyaminoacid.
 14. The injector as claimed in claim 13, wherein said polyaminoacid is polyglycolic acid.
 15. The injector as claimed in claim 13,wherein said polyamino acid is polylactic acid.
 16. The injector asclaimed in claim 1, wherein the polymer is in the form of a fibrousassembly.
 17. The injector as claimed in claim 16, wherein said fibrousassembly is an assembly of oxidized cellulose fiber.
 18. The injector asclaimed in claim 16, wherein said fibrous assembly is an assembly ofgelatin fiber.
 19. The injector as claimed in claim 16, wherein saidfibrous assembly is an assembly of chitin fiber.
 20. The injector asclaimed in claim 1, wherein said polymer is in the form of a sponge. 21.The injector as claimed in claim 20, wherein said sponge is oxidizedcellulose sponge.
 22. The injector as claimed in claim 20, wherein saidsponge is gelatin sponge.
 23. The injector as claimed in claim 20,wherein said sponge is chitin sponge.
 24. The injector as claimed inclaim 1, wherein said polymer is in the form of a powder.
 25. Theinjector as claimed in claim 24, wherein said powder is oxidizedcellulose powder.
 26. The injector as claimed in claim 24, wherein saidpowder is gelatin powder.
 27. The injector as claimed in claim 24,wherein said powder is chitin powder.
 28. The injector as claimed inclaim 1, wherein said polymer is in the form of a monofilament.
 29. Theinjector as claimed in claim 1, wherein said polymer is in the form of afilm.
 30. The injector as claimed in claim 1, wherein said polymer is inthe form of a microcapsule.
 31. The injector as claimed in claim 1,wherein said anti-cancer drug is an alkylating agent.
 32. The injectoras claimed in claim 1, wherein said anti-cancer drug is a combination ofcyclophosphamide, 5-fluorouracil and mitomycin.
 33. The injector asclaimed in claim 1, wherein said anti-cancer drug is a combination ofcyclophosphamide, 5-fluorouracil and bleomycin.
 34. The injector asclaimed in claim 1, wherein said anto-cancer drug is bleomycin.
 35. Theinjector as claimed in claim 1, wherein said antic-cancer drug ismitomycin C.
 36. The injector as claimed in claim 1, wherein saidanti-cancer drug is adriamycin.
 37. The injector as claimed in claim 1,wherein said anti-cancer drug is 5-fluorouracil.
 38. The injector asclaimed in claim 1, wherein said blood coagulation factor is FactorXIII.
 39. The injector as claimed in claim 1, wherein said bloodcoagulation factor is thrombin.
 40. The injector as claimed in claim 1,wherein said blood coagulation factor is a combination of Factor XIIIand thrombin.
 41. The injector as claimed in claim 1, wherein saidanti-cancer drug and blood coagulation factor are fixed to the polymerby covalently bonding to the polymer.
 42. The injector as claimed inclaim 1, wherein calcium ion is additionally fixed to said polymer. 43.The injector as claimed in claim 1, wherein a pharmaceutical isadditionally fixed to said polymer.
 44. The injector as claimed in claim43, wherein said pharmaceutical is selected from the group consisting ofprotease inhibitors, plasma proteins, fibronectin, antiboitics,antivirals, sulfanamides and anti-infectives.
 45. The injector asclaimed in claim 1, wherein said polymer is a bioabsorable polymer andwherein said polymer is in the form of a fibrous assembly.
 46. Theinjector as claimed in claim 1, wherein said polymer is a bioabsorablematerial and wherein said polymer is in the form of a sponge.
 47. Theinjector as claimed in claim 1, wherein said polymer is a bioabsorablematerial and wherein said polymer is in the form of a powder.
 48. Theinjector as claimed in claim 1, wherein said polymer is a bioabsorablematerial and wherein said polymer is in the form of a monofilament. 49.The injector as claimed in claim 1, wherein said polymer is abioabsorable material and wherein said polymer is in the form of a film.50. The injector as claimed in claim 1, wherein said polymer isbioabsorable material and wherein said polymer is in the form of amicrocapsule.
 51. The injector as claimed in claim 1, wherein saidpolymer is gelatin powder, said anti-cancer drug, and said bloodcoagulation factor are fixed to said polymer by ionic bonding,entrapping and adsorption, said anti-cancer drug is mitomycin C andwherein said blood coagulation factor is a combination of Factor XIIIand thrombin.
 52. The injector as claimed in claims 1, 6, 16, 20, 24,28, 29, 30, 45, 46, 47, 48, 49 or 50, wherein said anti-cancer drug andblood coagulation factor are fixed to said polymer by ionically bondingto said polymer.
 53. The injector as claimed in claims 1, 6, 16, 20, 24,28, 29, 30, 45, 46, 47, 48, 49 or 50, wherein said anti-cancer drug andblood coagulation factor are fixed to said polymer, by adsorption. 54.The injector as claimed in claims 1, 6, 16, 20, 24, 28, 29, 30, 45, 46,47, 48, 49 or 50, wherein said anti-cancer drug and blood coagulationfactor are fixed to said polymer by entrapping.